Crystalline forms of (-)-(1r,2r)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride

ABSTRACT

A hitherto unknown crystalline form of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride, pharmaceutical compositions containing the new crystalline form, methods of producing the new crystalline form, and a related method of use including treatment of, e.g., pain and/or urinary incontinence.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 16/909,123,filed Jun. 23, 2020, which is is a continuation of application Ser. No.16/600,884, filed on Oct. 14, 2019, now abandoned, which is acontinuation of application Ser. No. 16/172,100, filed on Oct. 26, 2018,now abandoned, which is a continuation of application Ser. No.15/951,838, filed on Apr. 12, 2018, now abandoned, which is acontinuation of application Ser. No. 15/725,967, filed on Oct. 5, 2017,now abandoned, which is a continuation application of application Ser.No. 15/428,613, filed on Feb. 9, 2017, now abandoned, which is acontinuation of application Ser. No. 14/930,337, filed on Nov. 2, 2015,now abandoned, which is a continuation of application Ser. No.14/304,313, filed on Jun. 13, 2014, now abandoned, which is acontinuation of application Ser. No. 13/923,891, filed on Jun. 21, 2013,now abandoned, which is continuation of application Ser. No. 13/565,867,filed Aug. 3, 2012, now abandoned, which is a continuation ofapplication Ser. No. 13/172,009, filed Jun. 29, 2011, now abandoned,which is a continuation of application Ser. No. 12/634,777, filed Dec.10, 2009, now U.S. Pat. No. 7,994,364, issued on Aug. 9, 2011, which isa continuation of application Ser. No. 12/274,747, filed Nov. 20, 2008,now abandoned, which is a continuation of application Ser. No.11/646,232, filed Dec. 28, 2006, now abandoned, which is a continuationof International patent application no. PCT/EP2005/006884, filed Jun.27, 2005, which claims benefit of European patent application Serial No.04015091.4 filed Jun. 28, 2004, the entire disclosures of each of whichare hereby incorporated in their entirety.

FIELD OF THE INVENTION

This invention relates to solid crystalline forms of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride compounds, methods of producing these compounds, andrelated treatments, including use as analgesics as well aspharmaceutical compositions containing these compounds.

BACKGROUND OF THE INVENTION

The treatment of pain conditions is of great importance in medicine.There is currently a world-wide need for additional pain therapy. Thepressing requirement for a target-oriented treatment of pain conditionswhich is right for the patient, which is to be understood as thesuccessful and satisfactory treatment of pain for the patients, isdocumented in the large number of scientific works which have recentlyand over the years appeared in the field of applied analgesics or onbasic research on nociception.

BRIEF SUMMARY OF THE INVENTION

One object of the present invention is to provide new solid forms of(−)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride useful in the treatment or inhibition of pain.

U.S. Pat. Nos. 6,248,737 and 6,344,558 as well as European Patent EP 693475 B1 disclose the substance and the synthesis of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride in example 25. As proven by X-ray diffraction the 1R,2Rconfiguration as shown in the drawing of the structure in example 25 iscorrect although the configuration is reported as (−)-(1R,2S) in U.S.Pat. No. 6,248,737 and (−)-(1S,2S) in U.S. Pat. No. 6,344,558 as well asin EP 693 475 B1.

It has now been surprisingly found that(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride can be produced in a reproducible manner in two differentcrystalline forms. The present invention provides a new form (Form A) of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride which is different from the form already known (Form B)obtained by the procedure described in example 25 of U.S. Pat. Nos.6,248,737 and 6,344,558 as well as EP 693 475 B1. This new Form A of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride is very stable at ambient conditions and therefore usefulfor producing a pharmaceutical composition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray diffraction pattern;

FIG. 2 shows an infrared spectrum;

FIG. 3 shows a RAMAN spectrum;

FIG. 4 shows an X-ray diffraction pattern;

FIG. 5 shows an infrared spectrum;

FIG. 6 shows a RAMAN spectrum;

FIG. 7 shows an X-ray diffraction pattern;

FIG. 8 shows an X-ray diffraction pattern

SUMMARY OF THE INVENTION

The new crystalline Form A of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride can be identified by X-ray powder diffraction. The X-raydiffraction (“XRPD”) pattern is shown in FIG. 1 with the peak listingshown as Table 1.

The most important X-ray lines (2-theta values) in terms of intensitycharacterizing Form A of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride showing one or a combination of the following in a powderdiffraction measurement when measured using Cu Kα radiation at ambienttemperature are 14.5±0.2, 18.2±0.2, 20.4±0.2, 21.7±0.2 and 25.5±0.2.

To discriminate crystalline Form A of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride from Form B it is more advantageous to look at the uniquepeaks in the X-ray diffraction diagram, i.e. e.g. the lines withsufficient intensity at 2-theta values, where Form B does not show lineswith significant intensity. Such characteristic X-ray lines (2-thetavalues) for Form A in a powder diffraction pattern when measured usingCuKα radiation at ambient temperature are: 15.1±0.2, 16.0±0.2, 18.9±0.2,20.4±0.2, 22.5±0.2, 27.3±0.2, 29.3±0.2 and 30.4±0.2.

Another method to identify crystalline Form A of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride is IR-spectroscopy. The IR-Spectrum of Form A is shown asFIG. 2 with the peak listing shown in comparism to Form B as Table 2.

In the IR-spectrum it is characteristic for crystalline Form A of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride to show a combination of the following IR bands: 3180±4cm⁻¹, 2970±4 cm⁻¹, 2695±4 cm⁻¹, 2115±4 cm⁻¹, 1698±4 cm⁻¹, 1462±4 cm⁻¹,1032±4 cm⁻¹ and/or 972±4 cm⁻¹.

RAMAN technique can also be used to identify of the crystalline Form Aof (−)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride. Especially the range between 800 cm⁻¹and 200 cm⁻¹, whichis shown in FIG. 3, is advantageously used also by way of RAMANmicroscopy.

Crystal structure analysis of Form A of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride showed monoclinic crystals with the following parametersof the elemental cell (length of side and angle):

-   -   a: 7.11 Å    -   b: 11.62 Å    -   c: 17.43 Å    -   β: 95.0°.

The elemental cell of the crystal of crystalline Form A has a volume of1434±5 Å³ and a calculated density of 1.20±0.01 g/cm³.

The invention further relates to processes for the preparation ofcrystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride.

The process starts from crystalline Form B of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride prepared according to U.S. Pat. Nos. 6,248,737 or6,344,558 or European Patent EP 693 475 B1 incorporated herein byreference.

In one embodiment of the process(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of crystalline Form A is produced by dissolving the(−)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of crystalline Form B in acetone, acetonitrile orisopropanol, optionally followed by filtering, leaving the solution tocrystallize and isolating the crystals of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride ofcrystalline Form A preferably by filtering again.

If acetone or acetonitrile is used it is preferred that during thisprocess the temperature is kept below +40° C., more preferably below+25° C., especially after filtering. It is further preferred that inthis process between 5 mg and 1 mg, more preferably between 2.5 mg and1.4 mg, especially between 2.0 mg and 1.4 mg (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride isdissolved per ml solvent.

The use of isopropanol is preferred, if seed crystals of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of crystalline Form A are available. The isopropanol usedpreferably contains about 0.5% per volume of water. The dissolution ofthe (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of crystalline Form B in isopropanol is performed attemperatures above room temperature, preferably above 65° C. but notexceeding 80° C. After complete dissolution the heat is turned of andthe seed crystals are added during a first cooling phase. Thereafter theresulting mixture is cooled down to ≤15° C., preferably ≤10° C. andespecially ≤5° C.

Optionally it is possible to reduce the solvent by evaporation,preferably in an evaporator under reduced pressure. Preferably theremaining volume of the solution after evaporation should not be lessthan 20% of the volume at the beginning of the process. Optionally it isalso possible to add active carbon to the solution originally prepared.

In a preferred embodiment of the invention the(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of crystalline Form A obtained by the process describedabove is redesolved in acetone acetonitrile or isopropanol, preferablyin the solvent already used in the first step, optionally is filtered toremove any insoluble residue and, optionally after reducing the amountof solvent by evaporation, is left to crystallize.

It is preferred that in the last crystallization step the temperature ismaintained at ≤15° C., more preferably ≤10° C. and especially ≤5° C.

In a further embodiment of the process according to the invention(−)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of crystalline Form A is produced in the solid state bycooling (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of crystalline Form B between 24 h and 168 h to atemperature between −4° C. and −80° C. It is preferred that in thisprocess the cooling temperature is between −10° C. and −60° C.,preferably between −15° C. and −50° C., especially between −25° C. and−40° C. and the cooling is carried out for a time between 24h and 120 h,preferably between 24h and 72 h, especially between 24 h and 48h.

This invention further relates to a new Crystalline Form A of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride obtainable by dissolving (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride ofForm B in acetonitrile together with active carbon, heating the solutionto the boiling point, removing the active carbon by filtering, stirringthe solution at a temperature below 40° C., removing insoluble residueby filtering and removing part of the solvent leaving(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of Form A to crystallize, redissolving the crystals soobtained in acetonitrile, removing insoluble residue by filtering andremoving part of the solvent leaving(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of Form A to crystallize.

Crystalline Form A according to the invention has the samepharmacological activity as Form B but is more stable under ambientconditions. It can be advantageously used as active ingredient inpharmaceutical compositions.

Therefore the invention further relates to a pharmaceutical compositioncontaining as active ingredient(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of crystalline Form A according to the invention and atleast one suitable additive and/or auxiliary substance.

Such pharmaceutical composition according to the invention contains, inaddition to crystalline Form A(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride, one or more suitable additive and/or auxiliary substancesuch as for example carrier materials, fillers, solvents, diluents,coloring agents and/or binders, and may be administered as liquidmedicament preparations in the form of injectable solutions, drops orjuices, as semi-solid medicament preparations in the form of granules,tablets, pellets, patches, capsules, plasters or aerosols. The choice ofthe auxiliary substances, etc., as well as the amounts thereof to beused depend on whether the medicament is to be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally,intramuscularly, intranasally, buccally, rectally or topically, forexample to the skin, the mucous membranes or the eyes. For oralapplication suitable preparations are in the form of tablets,sugar-coated pills, capsules, granules, droplets, juices and syrups,while for parenteral, topical and inhalative application suitable formsare solutions, suspensions, readily reconstitutable dry preparations, aswell as sprays. Form A in a depot form, in dissolved form or in aplaster, optionally with the addition of agents promoting skinpenetration, are suitable percutaneous application preparations.Preparation forms that can be administered orally or percutaneously canprovide for the delayed release of crystalline Form A according to theinvention. In principle further active constituents known to the personskilled in the art may be added to the medicaments according to theinvention.

Preferred formulations for crystalline Form A(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride according to the invention are presented in thePCT-application WO 03/035054 incorporated herein by reference.

The amount of active constituent to be administered to the patientvaries depending on the patient's weight, on the type of application,medical indication and severity of the condition. Normally 0.005 to 1000mg/kg, preferably 0.05 to 5 mg/kg of crystalline Form A according to theinvention are administered.

Preferably, the crystalline Form A according to the invention is usedfor the treatment of pain or the treatment of urinary incontinence.Accordingly the invention also relates to the use of crystalline Form Aaccording to the invention for the treatment of pain or the treatment ofurinary incontinence.

Additionally the invention relates to a method of treatment using asufficient amount of crystalline Form A according to the invention forthe treatment of a disease, especially pain or urinary incontinence.

Certain embodiments of the present invention may be further understoodby reference to the following specific examples. These examples and theterminology used herein are for the purpose of describing particularembodiments only and are not intended to be limiting.

EXAMPLE 1 Master Recipe for Preparation of Form A

The master recipe is valid for a 50 ml scale.

Provide 1.9 g (−)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride prepared according to example 25 ofEuropean Patent EP 693 475 B1 in a 50 ml glass round bottom vessel witha 3-blade overhead stirrer with baffles.

Add 25 ml isopropanol and 0.5% (v/v) water

Stir at 800 rpm

Heat to 80° C.

Hold temperature while stirring for 10 minutes

Cool to 65° C.

Add 0.056 g seeds (Mean Sq. Wt. CL=58 μm², Median No Wt. CL=22 μm)

Cool to 0° C. over 1 hour

Filter slurry through PTFE filter column (5 μm pore size)

Dry solid material under slight vacuum until constant weight (approx. 24hours)

Repeat the same procedure with the dry solid material obtained

EXAMPLE 2 Preparation of Form A (1)

(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride was prepared according to example 25 of European Patent EP693 475 B1. 32.2 mg of the thus synthesized(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride was—by slight heating up to 40° C. and/or agitating on anorbital shaker for 30 min—dissolved in 20 ml acetone. Following that thesolution was filtered through a nylon syringe filter having a mesh of0.20 gm and the solution was left to crystallize by slow evaporation ofthe solvent. Crystalline Form A of(−)-(1R,2R)-3-(3-dimethylamino-l-ethyl-2-methylpropyl)-phenolhydrochloride was generated as proven by X-ray powder diffraction and byRAMAN microscopic analysis.

EXAMPLE 3 Preparation of Form A (2)

(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride was prepared according to example 25 of European Patent EP693 475 B1. 32.2 mg of the thus synthesized(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride was—if necessary by agitating for e.g. 30 min—dissolved in20 ml acetone. Following that the solution was filtered with a nylonsyringe filter having a mesh of 0.20 μm and the solution was left tocrystallize by slow evaporation of the solvent. In no step after andincluding the dissolving the temperature was allowed to rise above +25°C. Crystalline Form A of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride was generated as proven by X-ray powder diffractionexperiment and by RAMAN microscopic analysis.

EXAMPLE 4 Preparation of Form A (3)

(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride was prepared according to example 25 of European Patent EP693 475 B1. 350 mg of the thus synthesized(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride were dissolved in 50 ml acetonitrile in a 250 ml flask.The mixture was stirred for 1.5 h on a water bath heated to 37° C.±1° C.Any insoluble residue was removed by filtering. Of the clear solution 35ml was removed on a rotation evaporator at 70-80 mbar and a temperatureof the water bath of 30° C.±1° C. The precipitated solid compound wasfiltered by vacuum. Crystalline Form A of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride was generated as proven by X-ray powder diffraction and byRAMAN microscopic analysis.

EXAMPLE 5 Preparation of Form A (4)

(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride was prepared according to example 25 of European Patent EP693 475 B1. The thus synthesized(−)-(1R,2R)-3-(3-dimethylamino-l-ethyl-2-methylpropyl)-phenolhydrochloride was stored for 72 h at −40° C. Crystalline Form A of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride was generated as proven by X-ray powder diffraction and byRAMAN microscopic analysis.

EXAMPLE 6 Preparation of Form A (5)

(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride was prepared according to example 25 of European Patent EP693 475 B1. 370 mg of the thus synthesized(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride were added to 40 ml acetonitrile and 100 mg active carbonin a 100 ml flask and heated to the boiling point. The active carbon wasfiltered off from the hot solution by means of a paper filter and thefiltrate concentrated to a volume of approx. 10 ml in a rotationevaporator at 150±10 mbar and 50° C. The solution was slowly rotated for30 minutes at room temperature. Following that the solution was allowedto stand for 30 minutes at room temperature and than for 1 hour at 4° C.The Crystals are filtered by vacuum through a glass filter (276 mgyield).

266 mg of these Crystals were dissolved at room temperature in 45 mlacetonitrile, insoluble residues were removed by filtration and thesolution was rotated for 1.5 h at 35-40° C. at atmospheric pressure in arotation evaporator. Than the solution was concentrated at 50° C. and150±10 mbar to a volume of approx. 10 ml and then slowly rotated for 30minutes at room temperature. Following that the flask was allowed tostand for 12 h at 4° C.

The precipitated solid is filtered by vacuum through a glass filter anddried in the air.

Yield:

151 mg (40.8% of the theory in relation to used educt), whitemicrocrystalline solid form

EXAMPLE 7 Preparation of Form B (1)

(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride was prepared according to example 25 of European Patent EP693 475 B1. Crystalline Form B of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride was generated as proven by X-ray powder diffraction and byRAMAN microscopic analysis.

EXAMPLE 8 Preparation of Form B (2)

(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride prepared according to one of the examples 1 to 5 wasmilled for at least 20 min. Then it was kept at 130° C. in an oven for80 min. Crystalline Form B of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride wasgenerated as proven by X-ray powder diffraction and by RAMAN microscopicanalysis.

EXAMPLE 9 Preparation of Form B (3)

(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride prepared according to one of the examples 1 to 5 wascryogrinded for at least 15 min. Then it was kept at 125° C. in a TGAfor 30 min. Crystalline Form B of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride wasgenerated as proven by X-ray powder diffraction and by RAMAN microscopicanalysis.

EXAMPLE 10 X-Ray Powder Diffraction Patterns of Forms A (1) and B (1)

Powder Data Collection was performed with a STOE Stadi P TransmissionPowder Diffractometer equipped with a curved germanium monochromator anda linear position sensitive detector. The very carefully ground powderswere prepared as flat samples. As source of the beam a copper X-ray tubewith monochromatized Cu Kα₁ (λ=1.54051 Å) radiation generated at 50 kVand 30 mA was used. The 20 area for the measurement was 5°-40°. The usedstep width was 0.02 degrees in 2 theta. The data were collected at atemperature of 23±1°.

The X-ray pattern for Form A is shown in FIG. 1, the X-ray pattern forForm B in FIG. 4.

The data are shown in Table 1.

TABLE 1 Peak and Relative Intensity Listing (°2θ, peaks with I/I1 valueof 10 and over) Peak No. A I/I1 B I/I1 1 9.07 10 14.58 100 2 10.11 914.94 9 3 14.51 100 15.42 19 4 15.08 24 15.76 27 5 15.39 11 16.05 8 615.69 22 16.77 14 7 15.96 24 18.01 60 8 16.62 13 19.60 39 9 17.00 2020.18 27 10 18.24 63 20.98 19 11 18.88 28 21.43 14 12 20.00 23 21.99 6513 20.39 47 23.71 4 14 21.66 47 24.73 43 15 22.54 41 25.10 14 16 24.2728 25.71 21 17 25.03 13 26.29 10 18 25.47 43 26.81 5 19 25.84 20 27.7620 20 26.04 27 28.19 39 21 26.94 13 29.20 12 22 27.29 29 29.86 13 2327.63 28 30.28 5 24 28.33 20 30.58 6 25 28.72 12 31.15 22 26 29.09 1232.41 6 27 29.29 21 32.91 5 28 29.76 11 33.17 6 29 30.37 23 34.34 6 3030.74 11 35.88 9 31 31.70 14 36.29 7 32 34.37 11 39.08 9

EXAMPLE 11 IR Spectrum of Forms A and B

The mid IR spectra were acquired on a Nicolet model 860 Fouriertransform IR spectrophotometer equipped with a globar source, Ge/KBrbeamsplitter, and deterated triglycine sulfate (DTGS) detector. ASpectra-Tech, Inc. diffuse reflectance accessory was utilized forsampling. Each spectrum represents 256 co-added scans at a spectralresolution of 4 cm⁻¹. A background data set was then acquired with analignment mirror in place. A single beam sample data set was thenacquired. Subsequently, a Log 1/R (R=Reflectance) spectrum was acquiredby rationing the two data sets against each other. The spectrophotometerwas calibrated (wavelength) with polystyrene at the time of use.

The spectrum for Form A is shown in FIG. 2. The spectrum for Form B isshown in FIG. 5.

The data are shown in the following Table 2.

TABLE 2 IR Peak Listing Form A Form B Peak Pos. Intensity Peak Pos.Intensity (cm⁻¹) (log 1/R) (cm⁻¹) (log 1/R) 3180.4 1.878 3170.2 2.1962970 1.856 3013.1 1.791 1462.1 1.848 2962.5 2.098 2695.2 1.841 2933.41.945 1600.9 1.838 2682 2.116 1281.6 1.771 1940.5 1.242 1378.3 1.7631870.7 1.246 1219.9 1.754 1801.7 1.201 1181.2 1.748 1749.5 1.236 1503.61.743 1598.1 2.138 1256.5 1.734 1503.2 1.755 712.6 1.725 1451.5 2.164879.8 1.713 1417.2 1.89 684.7 1.692 1396.3 1.843 798.7 1.681 1377.11.864 1313.6 1.673 1353.2 1.726 1005.1 1.655 1313.2 1.661 731.2 1.631280.7 1.977 1090.9 1.626 1254.8 1.973 810.2 1.622 1217.6 2.015 971.51.588 1177.5 1.868 842.6 1.576 1154.6 1.597 831.7 1.574 1136.4 1.4311111.5 1.55 1111.3 1.512 1049.8 1.534 1090.3 1.625 1136.5 1.498 1065.91.425 461.3 1.476 1049.9 1.52 1065.8 1.457 1004.6 1.813 495.1 1.438958.7 1.855 542.1 1.408 946.6 1.735 595.8 1.384 912.5 1.292 527.9 1.327877.8 1.951 912.4 1.304 842.7 1.657 1032.4 1.3 831.4 1.664 416.9 1.287810.7 1.715 1698.3 1.282 795.2 1.892 1940.5 1.279 730.6 1.855 1870.61.277 711.7 2.04 1749.4 1.268 683.4 1.917 1801.6 1.208 595.6 1.4392115.5 1.061 542.1 1.497 527.7 1.425 495.1 1.663 464.4 1.622 416.7 1.439

EXAMPLE 12 Single Crystal Structure Analysis of Form A

A colorless crystal of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenolhydrochloride prepared according to one of the examples 2 to 6 havingapproximate dimensions of 0.6×0.60×0.50 mm was mounted on a glass fiberin random orientation. Preliminary examination and data collection wereperformed with Cu Kα radiation (1.54184 Å) on a Enraf-Nonius CAD4computer controlled kappa axis diffractometer equipped with a graphitecrystal, incident beam monochromator.

Cell constants and an orientation matrix for data collection wereobtained from least-squares refinement using the setting angles of 25reflections in the range 16°<θ<24°, measured by the computer controlleddiagonal slit method of centering. The monoclinic cell parameters andcalculated volume are:

a=7.110(3), b=11.615(4), c=17.425(6) Å, β=95.00(3), V=1433.5(10) Å³. ForZ=4 and formula weight of 257.79 the calculated density is 1.20 g·cm⁹⁻³.The space group was determined to be P2₁ (No. 19).

The data were collected at a temperature of −103±5° C. using ω-θ scantechnique. The scan rate varied from 4 to 20°/min (in ω). The variablescan rate allows rapid data collection for intense reflections where afast scan rate is used and assures good counting statistics for weakreflections where a slow scan rate is used. Data were collected to amaximum of 2θ of 75.11°. The scan range (in°) was determined as afunction of θ to correct for the separation of the Kα doublet. The scanwidth was calculated as follows:

θ scan width=0.8+0.140 tan θ

Moving-crystal moving-counter background counts were made by scanning anadditional 25% above and below this range. Thus the ratio of peakcounting time to background counting time was 2:1. The counter aperturewas also adjusted as a function of θ. The horizontal aperture widthranged from 2.4 to 2.5 mm; the vertical aperture was set at 4.0 mm.

The data for Form A as collected in a commonly known “.cif”-document forcomplete reference of distances within the molecule are shown in Table3.

Table 3:

TABLE 3a Crystal data and structure refinement for Form_A.Identification code FormA Empirical formula C14 H24 Cl N O Formulaweight   257.79 Temperature 170(2) K Wavelength 1.54184 Å Crystal systemmonoclinic Space group P 21 Unit cell dimensions a = 7.110(3) Å alpha =90 deg. b = 11.615(4) Å beta = 95.00(3) deg. c = 17.425(6) Å gamma = 90deg. Volume 1433.5(10) Å³ Z  4 Density (calculated) 1.195 Mg/m³Absorption coefficient 2.230 mm⁻¹ F(000) 560 Theta range for datacollection 4.58 to 75.11 deg. Index ranges 0 <= h <= 8, −14 <= k <= 14,−21 <= 1 <= 21 Reflections collected 4531  Independent reflections 4531[R(int) = 0.0000] Refinement method Full-matrix least-squares on F²Data/restraints/parameters 4531/1/323 Goodness-of-fit on F²     1.035Final R indices [I > 2sigma(I)] R1 = 0.0588, wR2 = 0.1629 R indices (alldata) R1 = 0.0643, wR2 = 0.1673 Absolute structure parameter .027(19)Largest diff. peak and hole 0.686 and −0.696 e · Å⁻³

TABLE 3b Atomic coordinates (×10⁴) and equivalent isotropic displacementparameters (Å² × 10³) for Form_A. U(eq) is defined as one third of thetrace of the orthogonalized Uij tensor. x y z U(eq) Cl(1) 2148(1)3541(1) 9878(1) 29(1) Cl(2) 7279(1) 2551(1) 5089(1) 28(1) O(1) −588(5)5289(3) 9077(2) 36(1) N(1)  822(4) 3979(3) 4964(2) 22(1) O(2) 4799(4) 769(3) 5795(2) 36(1) N(2) 5722(5) 2083(3) 10053(2)  27(1) C(1) 2263(6)3215(4) 4667(2) 33(1) C(2)  −85(6) 4736(4) 4336(2) 31(1) C(3) 1580(5)4713(3) 5628(2) 22(1) C(4) 2627(5) 4056(3) 6291(2) 21(1) C(5) 1401(6)3130(4) 6613(2) 29(1) C(6) 3437(5) 4902(3) 6925(2) 22(1) C(7) 4927(5)5729(4) 6656(2) 27(1) C(8) 6603(6) 5138(4) 6351(3) 38(1) C(9) 1930(5)5552(3) 7326(2) 21(1) C(10) 1188(6) 6603(3) 7050(2) 25(1) C(11) −137(6)7175(3) 7448(2) 28(1) C(12) −739(6) 6733(4) 8117(2) 28(1) C(13)  −19(6)5686(4) 8404(2) 26(1) C(14) 1313(5) 5102(3) 8001(2) 23(1) C(20) 7093(7)2841(5) 10502(3)  41(1) C(21) 4877(7) 1235(5) 10570(3)  41(1) C(22)6542(6) 1458(3) 9408(2) 25(1) C(23) 7484(5) 2230(3) 8856(2) 22(1) C(24)6086(6) 3070(4) 8447(2) 29(1) C(25) 8541(5) 1512(3) 8274(2) 20(1) C(26)10222(6)   857(4) 8681(2) 28(1) C(27) 11528(6)   374(4) 8118(3) 36(1)C(28) 7250(5)  740(3) 7756(2) 22(1) C(29) 6682(5) −349(3) 7991(2) 24(1)C(30) 5507(5) −1019(3)  7501(2) 26(1) C(31) 4871(6) −654(3) 6769(2)26(1) C(32) 5427(6)  430(4) 6529(2) 26(1) C(33) 6604(5) 1116(4) 7018(2)24(1)

TABLE 3c Bond lengths [A] and angles [deg] for Form_A. O(1)—C(13)1.355(5) O(1)—H(1)   .86(11) N(1)—C(1) 1.482(5) N(1)—C(3) 1.499(5)N(1)—C(2) 1.504(5) N(1)—H(1A) .9100 O(2)—C(32) 1.374(5) O(2)—H(2) .90(9) N(2)—C(20) 1.485(6) N(2)—C(21) 1.495(6) N(2)—C(22) 1.497(5)N(2)—H(2A) .9100 C(1)—H(1A) .9801 C(1)—H(1B) .9801 C(1)—H(1C) .9801C(2)—H(2A) .9801 C(2)—H(2B) .9801 C(2)—H(2C) .9801 C(3)—C(4) 1.524(5)C(3)—H(3A) .9800 C(3)—H(3B) .9800 C(4)—C(5) 1.522(5) C(4)—C(6) 1.553(5)C(4)—H(4) .9800 C(5)—H(5A) .9801 C(5)—H(5B) .9801 C(5)—H(5C) .9801C(6)—C(9) 1.528(5) C(6)—C(7) 1.533(6) C(6)—H(6) .9800 C(7)—C(8) 1.511(6)C(7)—H(7A) .9800 C(7)—H(7B) .9800 C(8)—H(8A) .9801 C(8)—H(8B) .9801C(8)—H(8C) .9801 C(9)—C(14) 1.392(5) C(9)—C(10) 1.398(5) C(10)—C(11)1.386(6) C(10)—H(10) .9800 C(11)—C(12) 1.376(6) C(11)—H(11) .9800C(12)—C(13) 1.395(6) C(12)—H(12) .9800 C(13)—C(14) 1.402(5) C(14)—H(14).9800 C(20)—H(20A) .9801 C(20)—H(20B) .9801 C(20)—H(20C) .9801C(21)—H(21A) .9801 C(21)—H(21B) .9801 C(21)—H(21C) .9801 C(22)—C(23)1.513(5) C(22)—H(22A) .9800 C(22)—H(22B) .9800 C(23)—C(24) 1.525(5)C(23)—C(25) 1.556(5) C(23)—H(23) .9800 C(24)—H(24A) .9801 C(24)—H(24B).9801 C(24)—H(24C) .9801 C(25)—C(28) 1.523(5) C(25)—C(26) 1.537(5)C(25)—H(25) .9800 C(26)—C(27) 1.517(5) C(26)—H(26A) .9800 C(26)—H(26B).9800 C(27)—H(27A) .9801 C(27)—H(27B) .9801 C(27)—H(27C) .9801C(28)—C(33) 1.397(5) C(28)—C(29) 1.400(6) C(29)—C(30) 1.382(6)C(29)—H(29) .9800 C(30)—C(31) 1.381(6) C(30)—H(30) .9800 C(31)—C(32)1.395(6) C(31)—H(31) .9800 C(32)—C(33) 1.392(6) C(33)—H(33) .9800C(13)—O(1)—H(1)   116(6) C(1)—N(1)—C(3) 113.4(3) C(1)—N(1)—C(2) 111.2(3)C(3)—N(1)—C(2) 109.4(3) C(1)—N(1)—H(1A) 107.5 C(3)—N(1)—H(1A) 107.5C(2)—N(1)—H(1A) 107.5 C(32)—O(2)—H(2)   127(6) C(20)—N(2)—C(21) 110.7(4)C(20)—N(2)—C(22) 113.7(3) C(21)—N(2)—C(22) 109.6(3) C(20)—N(2)—H(2A)107.5 C(21)—N(2)—H(2A) 107.5 C(22)—N(2)—H(2A) 107.5 N(1)—C(1)—H(1A)109.5 N(1)—C(1)—H(1B) 109.5 H(1A)—C(1)—H(1B) 109.5 N(1)—C(1)—H(1C) 109.5H(1A)—C(1)—H(1C) 109.5 H(1B)—C(1)—H(1C) 109.5 N(1)—C(2)—H(2A) 109.5N(1)—C(2)—H(2B) 109.5 H(2A)—C(2)—H(2B) 109.5 N(1)—C(2)—H(2C) 109.5H(2A)—C(2)—H(2C) 109.5 H(2B)—C(2)—H(2C) 109.5 N(1)—C(3)—C(4) 114.8(3)N(1)—C(3)—H(3A) 108.6 C(4)—C(3)—H(3A) 108.6 N(1)—C(3)—H(3B) 108.6C(4)—C(3)—H(3B) 108.6 H(3A)—C(3)—H(3B) 107.6 C(5)—C(4)—C(3) 112.1(3)C(5)—C(4)—C(6) 111.9(3) C(3)—C(4)—C(6) 110.4(3) C(5)—C(4)—H(4) 107.4C(3)—C(4)—H(4) 107.4 C(6)—C(4)—H(4) 107.4 C(4)—C(5)—H(5A) 109.5C(4)—C(5)—H(5B) 109.5 H(5A)—C(5)—H(5B) 109.5 C(4)—C(5)—H(5C) 109.5H(5A)—C(5)—H(5C) 109.5 H(5B)—C(5)—H(5C) 109.5 C(9)—C(6)—C(7) 111.2(3)C(9)—C(6)—C(4) 114.0(3) C(7)—C(6)—C(4) 113.7(3) C(9)—C(6)—H(6) 105.7C(7)—C(6)—H(6) 105.7 C(4)—C(6)—H(6) 105.7 C(8)—C(7)—C(6) 114.2(4)C(8)—C(7)—H(7A) 108.7 C(6)—C(7)—H(7A) 108.7 C(8)—C(7)—H(7B) 108.7C(6)—C(7)—H(7B) 108.7 H(7A)—C(7)—H(7B) 107.6 C(7)—C(8)—H(8A) 109.5C(7)—C(8)—H(8B) 109.5 H(8A)—C(8)—H(8B) 109.5 C(7)—C(8)—H(8C) 109.5H(8A)—C(8)—H(8C) 109.5 H(8B)—C(8)—H(8C) 109.5 C(14)—C(9)—C(10) 118.7(3)C(14)—C(9)—C(6) 119.0(3) C(10)—C(9)—C(6) 122.2(3) C(11)—C(10)—C(9)119.9(4) C(11)—C(10)—H(10) 120.0 C(9)—C(10)—H(10) 120.0C(12)—C(11)—C(10) 121.3(4) C(12)—C(11)—H(11) 119.3 C(10)—C(11)—H(11)119.3 C(11)—C(12)—C(13) 119.8(4) C(11)—C(12)—H(12) 120.1C(13)—C(12)—H(12) 120.1 O(1)—C(13)—C(12) 118.6(4) O(1)—C(13)—C(14)122.3(4) C(12)—C(13)—C(14) 119.0(4) C(9)—C(14)—C(13) 121.2(3)C(9)—C(14)—H(14) 119.4 C(13)—C(14)—H(14) 119.4 N(2)—C(20)—H(20A) 109.5N(2)—C(20)—H(20B) 109.5 H(20A)—C(20)—H(20B) 109.5 N(2)—C(20)—H(20C)109.5 H(20A)—C(20)—H(20C) 109.5 H(20B)—C(20)—H(20C) 109.5N(2)—C(21)—H(21A) 109.5 N(2)—C(21)—H(21B) 109.5 H(21A)—C(21)—H(21B)109.5 N(2)—C(21)—H(21C) 109.5 H(21A)—C(21)—H(21C) 109.5H(21B)—C(21)—H(21C) 109.5 N(2)—C(22)—C(23) 114.4(3) N(2)—C(22)—H(22A)108.7 C(23)—C(22)—H(22A) 108.7 N(2)—C(22)—H(22B) 108.7C(23)—C(22)—H(22B) 108.7 H(22A)—C(22)—H(22B) 107.6 C(22)—C(23)—C(24)111.7(3) C(22)—C(23)—C(25) 111.3(3) C(24)—C(23)—C(25) 111.8(3)C(22)—C(23)—H(23) 107.3 C(24)—C(23)—H(23) 107.3 C(25)—C(23)—H(23) 107.3C(23)—C(24)—H(24A) 109.5 C(23)—C(24)—H(24B) 109.5 H(24A)—C(24)—H(24B)109.5 C(23)—C(24)—H(24C) 109.5 H(24A)—C(24)—H(24C) 109.5H(24B)—C(24)—H(24C) 109.5 C(28)—C(25)—C(26) 112.8(3) C(28)—C(25)—C(23)113.7(3) C(26)—C(25)—C(23) 111.4(3) C(28)—C(25)—H(25) 106.1C(26)—C(25)—H(25) 106.1 C(23)—C(25)—H(25) 106.1 C(27)—C(26)—C(25)112.3(3) C(27)—C(26)—H(26A) 109.1 C(25)—C(26)—H(26A) 109.1C(27)—C(26)—H(26B) 109.1 C(25)—C(26)—H(26B) 109.1 H(26A)—C(26)—H(26B)107.9 C(26)—C(27)—H(27A) 109.5 C(26)—C(27)—H(27B) 109.5H(27A)—C(27)—H(27B) 109.5 C(26)—C(27)—H(27C) 109.5 H(27A)—C(27)—H(27C)109.5 H(27B)—C(27)—H(27C) 109.5 C(33)—C(28)—C(29) 118.2(4)C(33)—C(28)—C(25) 119.6(3) C(29)—C(28)—C(25) 122.2(3) C(30)—C(29)—C(28)120.1(4) C(30)—C(29)—H(29) 120.0 C(28)—C(29)—H(29) 120.0C(31)—C(30)—C(29) 122.0(4) C(31)—C(30)—H(30) 119.0 C(29)—C(30)—H(30)119.0 C(30)—C(31)—C(32) 118.4(4) C(30)—C(31)—H(31) 120.8C(32)—C(31)—H(31) 120.8 O(2)—C(32)—C(31) 117.4(4) O(2)—C(32)—C(33)122.3(4) C(31)—C(32)—C(33) 120.3(4) C(28)—C(33)—C(32) 121.1(4)C(28)—C(33)—H(33) 119.5 C(32)—C(33)—H(33) 119.5

Symmetry transformations used to generate equivalent atoms:

TABLE 3d Hydrogen coordinates (×10⁴) and isotropic displacementparameters (Å² × 10³) for Form_A. x y z U(eq) H(1) −380(15) 4570(10)9180(5) 110(3) H(1A) −96 3523 5133 26 H(2) 5310(14) 1310(9) 5510(5)100(3) H(2A) 4770 2536 9841 32 H(1A) 1737 2848 4189 43 H(1B) 2630 26225051 43 H(1C) 3374 3671 4564 43 H(2A) 838 5299 4182 41 H(2B) −1162 51414525 41 H(2C) −523 4261 3891 41 H(3A) 525 5130 5827 29 H(3B) 2438 52875439 29 H(4) 3700 3668 6086 27 H(5A) 2110 2747 7048 38 H(5B) 1040 25636210 38 H(5C) 262 3484 6788 38 H(6) 4100 4422 7324 28 H(7A) 4328 62276252 35 H(7B) 5381 6223 7090 35 H(8A) 7580 5710 6270 49 H(8B) 6204 47615860 49 H(8C) 7111 4561 6723 49 H(10) 1604 6936 6577 32 H(11) −656 79087248 36 H(12) −1670 7153 8392 36 H(14) 1819 4364 8198 30 H(20A) 64843193 10927 54 H(20B) 7521 3445 10166 54 H(20C) 8179 2384 10710 54 H(21A)4403 1642 11006 53 H(21B) 5842 677 10760 53 H(21C) 3833 830 10281 53H(22A) 5532 1026 9118 32 H(22B) 7472 900 9629 32 H(23) 8433 2688 9162 29H(24A) 5114 2639 8133 38 H(24B) 6755 3580 8115 38 H(24C) 5491 3530 883038 H(25) 9081 2070 7933 26 H(26A) 10938 1379 9040 37 H(26B) 9748 2248982 37 H(27A) 10856 −210 7794 46 H(27B) 12632 24 8403 46 H(27C) 11941997 7792 46 H(29) 7118 −637 8505 31 H(30) 5114 −1776 7677 34 H(31) 4048−1144 6428 34 H(33) 6986 1876 6842 31

TABLE 3e Anisotropic displacement parameters (Å² × 10³) for Form_A. Theanisotropic displacement factor exponent takes the form: −2 pi² [h² a*²U11 + . . . + 2 h k a* b* U12] U11 U22 U33 U23 U13 U12 Cl(1) 23(1) 27(1)36(1) −3(1) −1(1) 4(1) Cl(2) 23(1) 25(1) 35(1) −2(1) −2(1) −5(1)  O(1)35(2) 41(2) 33(2)  7(1) 8(1) 13(1)  N(1) 19(2) 28(2) 18(1)  1(1) −4(1)−5(1)  O(2) 33(2) 52(2) 21(1)  5(1) −11(1) −12(2)  N(2) 22(2) 31(2)27(2)  2(1) 2(1) 8(1) C(1) 29(2) 44(2) 26(2) −6(2) 1(2) 6(2) C(2) 25(2)41(2) 26(2) 11(2) −8(2) −4(2)  C(3) 20(2) 20(2) 26(2)  2(1) −4(1) −4(1) C(4) 19(2) 23(2) 20(2) −1(1) −2(1) 3(1) C(5) 33(2) 25(2) 28(2)  2(2)−3(2) −4(2)  C(6) 17(2) 26(2) 20(2) −2(1) −6(1) 6(1) C(7) 18(2) 30(2)32(2) −10(2)  −6(1) 0(2) C(8) 20(2) 40(2) 54(3) −11(2)  5(2) −3(2)  C(9)18(2) 26(2) 19(2) −6(1) −7(1) 1(1) C(10) 23(2) 24(2) 26(2)  0(2) −4(1)1(1) C(11) 23(2) 28(2) 32(2)  0(2) −9(2) 5(2) C(12) 20(2) 31(2) 32(2)−5(2) −1(2) 5(2) C(13) 22(2) 33(2) 24(2)  0(2) −2(1) 3(2) C(14) 20(2)24(2) 25(2)  0(2) −5(1) 5(1) C(20) 40(3) 51(3) 32(2) −12(2)  −3(2)−1(2)  C(21) 39(3) 49(3) 37(2) 10(2) 16(2) 10(2)  C(22) 27(2) 23(2)25(2) −1(2) 2(2) 2(2) C(23) 21(2) 22(2) 22(2) −2(1) −3(1) 2(1) C(24)32(2) 27(2) 27(2)  2(2) −1(2) 8(2) C(25) 15(2) 24(2) 20(2)  1(1) −3(1)1(1) C(26) 21(2) 33(2) 30(2) −2(2) −4(2) 6(2) C(27) 25(2) 39(2) 43(2) 1(2) 4(2) 7(2) C(28) 18(2) 27(2) 21(2) −1(2) 1(1) 5(1) C(29) 22(2)25(2) 25(2) −1(2) 1(1) 3(1) C(30) 24(2) 22(2) 33(2) −4(2) 6(2) −1(2) C(31) 19(2) 31(2) 28(2) −10(2)  1(1) −2(2)  C(32) 21(2) 35(2) 21(2)−2(2) 2(1) −2(2)  C(33) 17(2) 30(2) 25(2)  1(2) 1(1) −4(1) 

EXAMPLE 13 Single Crystal Structure Analysis of Form B

A colorless chunk of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride prepared according to one of the examples 7 to 9 havingapproximate dimensions of 0.44×0.40×0.35 mm was mounted on a glass fiberin random orientation. Preliminary examination and data collection wereperformed with Mo Kα radiation (λ=0.71073 Å) on a Nonius KappaCCDdiffractometer.

Cell constants and an orientation matrix for data collection wereobtained from least-squares refinement using the setting angles of 6172reflections in the range 5<θ<27°. The orthorhombic cell parameters andcalculated volume are: a=7.0882(3), b=11.8444(6), c=17.6708(11) Å,V=1483.6(2) Å³. For Z=4 and formula weight of 257.79 the calculateddensity is 1.15 g·cm⁻³. The refined mosaicity from DENZO/SCALEPACK was0.68° (<1 mod, <2 poor) indicating moderate crystal quality. The spacegroup was determined by the program ABSEN. From the systematic presenceof:

-   -   h00 h=2n    -   0k0 k=2n    -   001 1=2n        and from subsequent least-squares refinement, the space group        was determined to be P2₁2₁21 (number 19).

The data were collected to a maximum 2θ value of 55.0°, at a temperatureof 343±1 K.

The data from examples 12 and 13 are compared in Table 3f:

TABLE 3f Form A (monoklin) Form B (orthorhombic) Formula C14 H24 Cl N OC14 H24 Cl N O M.W./g/mol 257.79 257.79 Space group No. 4, P2₁ No. 19,P2₁2₁2₁ Z (No. of Units) 4 4 a/Å 7.110(3) 7.0882(3) b/Å 11.615(4)11.8444(6) c/Å 17.425(6) 17.6708(11) α/° 90 90 β/° 95.00(3) 90 γ/° 90 90Volume of elementary 1434 1484 cell/Å³ Density (calc.)/g/cm³ 1.20 1.15

The data for Form B as collected in a commonly known “.cif”-document forcomplete reference of distances within the molecule are shown belowTable 4:

Table 4:

TABLE 4a Crystal data and structure refinement for Form_B.Identification code FormB Empirical formula C14 H2 H22 Cl N O Formulaweight   257.79 Temperature 343 K Wavelength .71073 Å Crystal systemorthorhombic Space group P 21 21 21 Unit cell dimensions a = 7.0882(3) Åalpha = 90 deg. b = 11.8444(6) Å beta = 90 deg. c = 17.6708(11) Å gamma= 90 deg. Volume 1483.56(13) Å³ Z  4 Density (calculated) 1.154 Mg/m³Absorption coefficient 0.244 mm⁻¹ F(000) 560 Theta range for datacollection 5.04 to 27.49 deg. Index ranges −9 <= h <= 9, −15 <= k <= 15,−22 <= 1 <= 22 Reflections collected 3207  Independent reflections 3207[R(int) = 0.0000] Refinement method Full-matrix least-squares on F²Data/restraints/parameters 3207/0/167 Quality-of-fit on F²     1.012Final R indices [I > 2sigma(I)] R1 = 0.0440, wR2 = 0.1137 R indices (alldata) R1 = 0.0598, wR2 = 0.1246 Absolute structure parameter −.03(8)Extinction coefficient .033(7) Largest diff. peak and hole 0.265 and−0.202 e · Å⁻³

TABLE 4b Atomic coordinates (×10⁴) and equivalent isotropic displacementparameters (Å² × 10³) for Form_B. U(eq) is defined as one third of thetrace of the orthogonalized Uij tensor. x y z U(eq) Cl 7978(1) −1959(1) 7646(1) 74(1) O(33) 4870(3)  85(2) 3443(1) 94(1) N(6) 5522(3) 1571(2) 7545(1) 64(1) C(1) 11558(4)  −160(3)  5596(2) 98(1) C(2) 10168(3) 333(2) 6149(2) 75(1) C(3) 8514(3) 925(2) 5758(1) 58(1) C(4) 7395(3)1654(2)  6327(1) 58(1) C(5) 6394(3) 922(2) 6909(1) 64(1) C(6) 4611(5)782(3) 8089(2) 96(1) C(7) 6834(5) 2342(3)  7943(2) 95(1) C(31) 7273(3)131(2) 5286(1) 57(1) C(32) 6643(3) 472(2) 4583(1) 61(1) C(33) 5509(3)−219(2)  4138(1) 68(1) C(34) 5050(3) −1291(2)  4395(2) 74(1) C(35)5679(4) −1637(2)  5098(2) 75(1) C(36) 6782(3) −946(2)  5542(1) 66(1)C(41) 6029(4) 2461(2)  5931(2) 80(1)

TABLE 4c Bond lengths [A] and angles [deg] for Form_B. O(33)—H(33) .76(3) O(33)—C(33) 1.358(3) N(6)—H(6)  .82(2) N(6)—C(7) 1.481(4)N(6)—C(6) 1.488(3) N(6)—C(5) 1.496(3) C(1)—C(2) 1.505(4) C(2)—C(3)1.531(3) C(3)—C(31) 1.534(3) C(3)—C(4) 1.546(3) C(4)—C(5) 1.520(3)C(4)—C(41) 1.530(3) C(31)—C(32) 1.381(3) C(31)—C(36) 1.396(3)C(32)—C(33) 1.391(3) C(33)—C(34) 1.387(4) C(34)—C(35) 1.382(4)C(35)—C(36) 1.377(4) H(33)—O(33)-C(33)  118(3) H(6)—N(6)—C(7)  104.9(15)H(6)—N(6)—C(6)  108.8(16) C(7)—N(6)—C(6) 110.7(2) H(6)—N(6)—C(5) 107.8(16) C(7)—N(6)—C(5) 114.5(2) C(6)—N(6)—C(5) 110.0(2)C(1)—C(2)—C(3) 112.7(3) C(2)—C(3)—C(31) 113.8(2) C(2)—C(3)—C(4) 110.8(2)C(31)—C(3)—C(4) 113.71(16) C(5)—C(4)—C(41) 111.75(18) C(5)—C(4)—C(3)111.13(17) C(41)—C(4)—C(3) 112.08(19) N(6)—C(5)—C(4) 114.03(18)C(32)—C(31)—C(36) 118.5(2) C(32)—C(31)—C(3) 119.66(19) C(36)—C(31)—C(3)121.8(2) C(31)—C(32)—C(33) 121.6(2) O(33)—C(33)—C(34) 117.5(2)O(33)—C(33)—C(32) 123.2(2) C(34)—C(33)—C(32) 119.3(2) C(35)—C(34)—C(33)119.3(2) C(36)—C(35)—C(34) 121.2(2) C(35)—C(36)—C(31) 120.0(2)

Symmetry transformations used to generate equivalent atoms:

TABLE 4d Hydrogen coordinates (×10⁴) and isotropic displacementparameters (Å² × 10³) for Form_B. x y z U(eq) H(33) 5160(4) 660(2)3290(2)  80(10) H(6) 4710(3) 1983(17) 7365(13) 54(6)  H(1A) 10962 −7535313 148 H(1B) 12620 −460 5867 148 H(1C) 11980 419 5256 148 H(2A) 10815871 6472 90 H(2B) 9682 −266 6469 90 H(3) 9079 1455 5398 70 H(4) 83122119 6602 70 H(5A) 5415 492 6655 76 H(5B) 7293 388 7117 76 H(6A) 3594393 7842 144 H(6B) 4128 1200 8512 144 H(6C) 5524 243 8264 144 H(7A) 79071923 8120 143 H(7B) 6200 2680 8366 143 H(7C) 7246 2922 7601 143 H(32)6984 1181 4403 74 H(34) 4325 −1772 4097 88 H(35) 5352 −2351 5274 90H(36) 7200 −1195 6012 79 H(41A) 5030 2036 5700 120 H(41B) 6693 2879 5549120 H(41C) 5506 2975 6295 120

TABLE 4e Anisotropic displacement parameters (Å² × 10³) for Form_B. Theanisotropic displacement factor exponent takes the form: −2 pi² [h² a*²U11 + . . . + 2 h k a* b* U12] U11 U22 U33 U23 U13 U12 Cl 71(1) 66(1)86(1) 5(1) −1(1) −13(1)  O(33) 102(1)  107(2)  74(1) 12(1)  −17(1) −43(1)  N(6) 63(1) 68(1) 59(1) 6(1)  3(1) 15(1) C(1) 68(1) 106(2) 122(3)  −12(2)  14(2) 17(2) C(2) 52(1) 86(2) 85(2) −1(1)  −1(1) 12(1)C(3) 52(1) 64(1) 60(1) 5(1)  4(1) −2(1) C(4) 62(1) 54(1) 59(1) 4(1)−1(1)  1(1) C(5) 68(1) 58(1) 65(1) 5(1)  9(1)  9(1) C(6) 102(2)  100(2) 87(2) 23(2)  33(2) 14(2) C(7) 95(2) 118(2)  73(2) −21(2)  −12(2)   0(2)C(31) 53(1) 58(1) 59(1) 2(1) 12(1)  4(1) C(32) 60(1) 63(1) 61(1) 0(1) 8(1) −8(1) C(33) 64(1) 81(2) 58(1) −3(1)   7(1) −14(1)  C(34) 69(1)71(1) 81(2) −11(1)  15(1) −16(1)  C(35) 87(2) 58(1) 80(2) 1(1) 24(1)−3(1) C(36) 72(1) 58(1) 67(1) 4(1) 13(1)  6(1) C(41) 96(2) 71(1) 73(2)14(1)   5(1) 24(1)

EXAMPLE 14 RAMAN Spectrum of Forms A and B

Form A and B were investigated using RAMAN spectroscopy. The RAMANspectrometer used was a Bruker Raman FT 100. The RAMAN Microscope was aRenishaw 1000 System, 20× Obj. Long working distance, diode laser 785nm. Raman spectroscopy was able to distinguish clearly between Forms Aand B. Differences between the spectra of the two forms appear in thewhole spectral range (3200-50 cm⁻¹), but the difference in the rangebetween 800-200 cm-1 were most significant.

The results for Form A are shown in FIG. 3, the results for Form B inFIG. 6.

Furthermore the samples were investigated by RAMAN microscopy. Thespectra of both forms were also distinguishable. Here, spectra weretaken in the wavenumber range of 2000-100 cm⁻¹.

EXAMPLE 16 Variable Temperature X-Ray Powder Diffraction Experiment

A variable temperature X-ray powder diffraction experiment was runthereby producing Form B from Form A. Form A converted to Form B from40-50° C. during the experiment. The result is reversible with Form Bchanging over into Form A at lower temperature.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

1. A process for producing a(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of crystalline Form A, said process comprising: dissolvinga (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of crystalline Form B in acetone, acetonitrile orisopropanol to form a solution; leaving the solution to crystallize andisolating crystals of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of crystalline Form A.
 2. The process of claim 1, whereinsaid (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of Form B is dissolved in acetonitrile, and furthercomprising the steps of: stirring the solution; removing insolubleresidue by filtering and evaporating the acetonitrile leaving(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of Form A to crystallize.
 3. The process according toclaim 1, wherein said(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of crystalline Form B is dissolved in isopropanol attemperatures above room temperature, and after complete dissolution nofurther heat is provided and further comprising: adding seed crystals of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of crystalline Form A and then cooling the mixture down to≤15° C.
 4. The process of claim 3, wherein said(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of crystalline Form B is dissolved in isopropanol at atemperature above 65° C. but not exceeding 80° C.
 5. The process ofclaim 3, wherein said mixture is cooled down to ≤10° C.
 6. The processof claim 3, wherein said mixture is cooled down to ≤5° C.
 7. The processaccording to claim 1, further comprising redissolving the(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of crystalline Form A in a solvent selected from acetone,acetonitrile and isopropanol, then optionally filtering the solution toremove any insoluble residue and optionally reducing the amount ofsolvent by evaporation, then allowing the solution to crystallize. 8.The process of claim 7, wherein said solvent is the same as that used toform the (−)-(1R, 2 R)-3-(3 -dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A before thestep of redissovling.
 9. The process of claim 7, wherein during the stepof allowing the solution to crystallize, the temperature is maintainedat ≤15° C.
 10. The process of claim 7, wherein during the step ofallowing the solution to crystallize, the temperature is maintained at≤10° C.
 11. The process of claim 7, wherein during the step of allowingthe solution to crystallize, the temperature is maintained at ≤5° C. 12.A crystalline Form A of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride produced by the process of: dissolving(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of Form B in acetonitrile together with active carbon,heating the solution to the boiling point, removing the active carbon byfiltering, stirring the solution at a temperature below 40° C., removinginsoluble residue by filtering and removing part of the solvent, leaving(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of Form A to crystallize, redissolving the resultingcrystals in acetonitrile, removing insoluble residue by filtering andremoving part of the solvent, and leaving(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of Form A to crystallize.
 13. A pharmaceutical compositioncomprising, as an active ingredient, a crystalline Form A of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride exhibiting at least X-ray lines (2-theta values) in apowder diffraction pattern when measured using Cu K_(α) radiation at15.1±0.2, 16.0±0.2, 18.9±0.2, 20.4±0.2, 22.5±0.2, 27.3±0.2, 29.3±0.2 and30.4±0.2, and at least one suitable additive or auxiliary substance. 14.A pharmaceutical composition comprising, as an active ingredient, acrystalline Form A of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride produced by the process of dissolving(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of Form B in acetonitrile together with active carbon,heating the solution to the boiling point, removing the active carbon byfiltering, stirring the solution at a temperature below 40° C., removinginsoluble residue by filtering and removing part of the solvent, leaving(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of Form A to crystallize, redissolving the resultingcrystals in acetonitrile, removing insoluble residue by filtering andremoving part of the solvent, and leaving(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride of Form A to crystallize, and at least one suitableadditive or auxiliary substance.